The restoration of the structural and functional integrity of tissue following acute injury is dependent on the interactions of cells, the extracellular matrix and soluble mediators. As a direct result of an increased understanding of the mechanisms by which these interactions occur new therapeutic interventions have are being designed to improve and accelerate clinical recovery. In contrast to acute wound healing, the biology of the chronic, non-healing wound, a frequently encountered clinical problem, is poorly understood. This ignorance is fostered in part by the absence of animal models that adequately mimic the chronic non- healing wounds found in clinical practice. Chronic cutaneous ulcers are often encountered in morbid states in which vascular compromise occurs as seen in the diabetic and elderly, atherosclerotic patients. Extravasation of the chemotherapeutic agents doxorubicin and vincristine result in the formation of extensive nonhealing wounds as does envenomation by the brown recluse (BR) spider (Loxosceles reclusa), indigenous to the southeastern United States. The objective of this proposal is to study the role of selected cytokines; transforming growth factor beta (TGFbeta), basic fibroblast growth factor (bFGF), platelet derived growth factor (PDGF) and transforming growth factor alpha (TGFalpha) on the synthesis of the extracellular matrix (collagen, elastin and fibronectin), matrix resorption by the metalloproteinases collagenase (which degrade fibrillar collagen) and stromelysin (which degrades fibronectin, laminin and cartilage proteoglycan) and metalloproteinase inhibition by tissue inhibitor of metalloproteinase (TIMP) in the context of a chronic non-healing wound. To this end we propose to develop an animal model based on the chronic wound that occurs following envenomation by the brown recluse (BR) spider (Loxosceles reclusa). As a result of these studies we expect to increase our understanding of the influence(s) of these cytokines on the cells of the chronic wound and, in turn, on the accumulation and resorption of the extracellular matrix. In addition, based on our experience with wound healing following acute injury, we expect to be able to develop a strategy in which the structural integrity of the healed wound can be enhanced and healing accelerated by either the exogenous administration of one or a combination of cytokines or the autogenous overexpression of a cytokine in situ.